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Collection of tumor samples is not always feasible in non-small cell lung cancer (NSCLC) patients, and circulating free DNA (cfDNA) extracted from blood represents a viable alternative. Different sensitive platforms have been developed for genetic cfDNA testing, some of which are already in clinical use. However, several difficulties remain, particularly the lack of standardization of these methodologies. Areas covered: Here, the authors present a review of the literature to update the applicability of cfDNA for diagnosis and monitoring of NSCLC patients. Expert commentary: Detection of somatic alterations in cfDNA is already in use in clinical practice and provides valuable information for patient management. Monitoring baseline alterations and emergence of resistance mutations is one of the most important clinical applications and can be used to non-invasively track disease evolution. Today, different technologies are available for cfDNA analysis, including whole-genome or exome sequencing and targeted methods that focus on a selection of genes of interest in a specific disease. In the case of Next Generation Sequencing (NGS) approaches, in depth coverage of candidate mutation loci can be achieved by selecting a limited number of targeted genes.

Mariacarmela Santarpia,1 Alessia Liguori,1 Niki Karachaliou,2 Maria Gonzalez-Cao,3 Maria Grazia Daffinà,1 Alessandro D’Aveni,1 Grazia Marabello,1 Giuseppe Altavilla,1 Rafael Rosell3–5 1Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy; 2Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, 3Department of Oncology, Institute of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, 4Cancer Biology and Precision Medicine Program, Germans Trias i Pujol Research Institute, 5Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Spain Abstract: The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care forEGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of theEGFRgene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-typeEGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment ofEGFRT790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I–III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome ofEGFR-mutated NSCLC patients. Keywords: osimertinib, T790M mutation, epidermal growth factor receptor, tyrosine kinase inhibitors

[This corrects the article DOI: 10.18632/oncotarget.25478.].

Background: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the coexistence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). Methods: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. Results: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. Conclusion: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC. (c) 2019 S. Karger AG, Basel

Identification of epidermal growth factor receptor (EGFR) as a molecular target has radically changed the treatment of metastatic non-small cell lung cancer (NSCLC) from standard chemotherapy to personalized, targeted therapy. First-, second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) are now available for the treatment of EGFR-mutant NSCLC patients. This review will focus on the clinical development of first-and second-generation EGFR TKIs. We will emphasize on essential points like the head-to-head comparison among EGFR TKIs, their activity on brain metastases, mechanisms of resistance, as well as their combination with anti-angiogenic compounds, other targeted therapies, or immunotherapy. The efficacy of first-and second-generation EGFR TKIs in early-stage EGFR-mutant NSCLC will be also finally reviewed.

Objectives: This study aims to determine the association of EGFR/KRAS mutation status with histological subtypes of lung adenocarcinoma (LAC) based on the IASLC/ATS/ERS classification. Methods: Pubmed and Cochrane databases were searched from January 2011 to June 2018 for studies that included patients with LAC who underwent surgical resection were classified according to the new IASLC/ATS/ERS classification. EGFR/KRAS status assessment was requireded. The primary outcome was determined by the odds ratio (OR) of the incidence of mutation status of certain of each histological subtype. The reference group consisted of EGFR/KRAS mutation negative patients. Results: Twenty-seven eligible studies involving 9022 patients with mutation gene detection were included for analysis. Among them, 6717 (74.5%) patients were from the Asian region and, 2305 (25.5%) patients were from Non-Asian regions. The most prevalent subtype was acinar (34.7%), followed by papillary (22.9%), lepidic (18.9%), solid (13.6%), micropapillary (6.3%), and invasive mucinous adenocarcinoma (3.5%). EGFR mutations were more common in patients with resected lepidic predominant adenocarcinoma (OR,1.76; 95%CI, 1.38-2.24;p < 0.01) and were rarely found in solid predominant adenocarcinoma (OR,0.28; 95%CI, 0.23-0.34:p < 0.01) or IMA (OR,0.10; 95%CI, 0.06-0.14;p < 0.01). Conversely, KRAS mutations were characterized by IMA (OR,7.01; 95%CI, 5.11-9.62;p < 0.01), and were less frequently identified in lepidic (OR,0.58; 95%CI, 0.45-0.75:p < 0.01) and acinar (OR,0.65; 95%CI, 0.55-0.78;p < 0.01) predominant subtypes. Further analyses were performed in Asian and Non-Asian groups and the results were consistent. Conclusions: The current study confirms that the IASLC/ATS/ERS classification is associated with driver gene alterations in resected LAC. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Epidermal growth factor receptor (EGFR) signaling deregulation promotes cancer stem cell (CSC) enrichment in non small-cell lung cancer (NSCLC). In vitro experiments showed that inhibition of EGFR, signal transducer and activator of transcription 3 (STAT3), and Src decreased the CSC subpopulation. High expression of aldehyde dehydrogenase (ALDH) 1 isoforms and target hairy and enhancer of split 1 (HES1) was predictive of worse outcome to EGFR inhibition in EGFR-mutation positive NSCLC patients. ALDH1, HES1, and B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) could be useful as biomarkers to monitor clinical progression, and the use of STAT3 and Src inhibitors could be useful to inhibit the CSC subpopulation induced by EGFR inhibitor treatment. Introduction: Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in non-small-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem cells (CSCs). Src through Yes-associated protein 1 (YAP1) activates NOTCH. Signal transduction and activator of transcription 3 (STAT3) activation occurs upon EGFR blockade and regulates the generation of CSCs. Patients and Methods: Using the Aldefluor assay kit, we investigated the enrichment of aldehyde dehydrogenase (ALDH)-positive cells in EGFRmutation-positive cells treated with gefitinib, afatinib, and osimertinib. Western blot analysis was performed to evaluate changes in CSC marker expression upon EGFR blockade. We performed gene expression analysis in a cohort of EGFR-mutation-positive non-small-cell lung cancer patients. We evaluated the association of gene expression with treatment outcomes. Results: The cell subpopulation surviving EGFR inhibition had high ALDH activity and elevated CSC marker expression. Concurrent inhibition of EGFR, STAT3, and Src diminished the CSC subpopulation in an EGFR-mutation-positive cellular model. In a cohort of 64 EGFR-mutation-positive patients, 2 ALDH1 isoforms and the NOTCH target hairy and enhancer of split 1 (HES1), when highly expressed, were predictive of worse outcome to EGFR blockade. The gene expression of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) that maintains the self-renewal of stem cells was also related to treatment outcome. Conclusion: Single EGFR inhibitors increase the population of CSCs. Combinatory therapy targeting STAT3 and Src may be of potential benefit. ALDH1, HES1, and Bmi-1 are essential biomarkers in the initial assessment of EGFR-mutation-positive patients. (C) 2019 Elsevier Inc. All rights reserved.

BACKGROUND: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. METHODS: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. RESULTS: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. CONCLUSIONS: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. Methods: The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKC iota) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-niive and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. Results: The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKC iota, ERK, AKT, STAT3, Src, and YAP1 were abrogated. Conclusions: The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of its levels increases cancer susceptibility. While the most validated anti-oncogenic duty of PTEN is the negative regulation of the PI3K/mTOR/Akt oncogenic signaling pathway, further tumor suppressor functions, such as chromosomal integrity and DNA repair have been reported. PTEN protein loss is a frequent event in lung cancer, but genetic alterations are not equally detected. It has been demonstrated that its expression is regulated at multiple genetic and epigenetic levels and deeper delineation of these mechanisms might provide fertile ground for upgrading lung cancer therapeutics. Today, PTEN expression is usually determined by immunohistochemistry and low protein levels have been associated with decreased survival in lung cancer. Moreover, available data involve PTEN mutations and loss of activity with resistance to targeted treatments and immunotherapy. This review discusses the current knowledge about PTEN status in lung cancer, highlighting the prevalence of its alterations in the disease, the regulatory mechanisms and the implications of PTEN on available treatment options.

Background: Reports regarding liquid biopsy and gastric cancer (GC) have emerged rapidly in recent decades, yet their prognostic value still remains controversial. This study was aimed to assess the impact of liquid biopsy, including circulating tumor cells (CTCs) and cell-free nucleic acids, on GC patients' prognosis. Methods: PubMed, Medline, EMBASE, and ClinicalTrial.gov databases were searched for studies that report GC patient survival data stratified by CTC/circulating tumor DNA (ctDNA)/circulating miRNAs' status. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for patients' overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were recorded or calculated depending on circulating target status. Results: We initially identified 4,221 studies, from which 43 were eligible for further analysis, comprising 3,814 GC patients. Pooled analyses showed that detection of certain CTCs, ctDNA, and circulating miRNA was associated with poorer OS (CTCs: HR = 1.84, 95%CI 1.50-2.26, p < 0.001; ctDNA: HR = 1.78, 95%CI 1.36-2.34, p < 0.001; circulating miRNA: HR = 1.74, 95%CI 1.13-2.69, p < 0.001) and DFS/PFS (CTCs: HR = 3.39, 95%CI 2.21-5.20, p < 0.001; ctDNA: HR = 2.38, 95%CI 1.31-4.32, p = 0.004; circulating miRNA: HR = 3.30, 95%CI 2.39-4.55, p < 0.001) of GC patients, regardless of disease stage and time point at which sample is taken (at baseline or post-treatment). Conclusions: The presence of CTCs and/or cellular components identifies a group of GC with poorer prognosis. Among circulating markers, CTCs demonstrated a stronger and more stable predictive value for late-stage disease and among Mongolian populations with GC. Less data are available for ctDNA and miRNA; however, their presence may also reflect aggressive biology and warrants further prospective study.